CS267331B1 - Method 1 for the preparation of 1- (5-oxohexyl) -3-methyl-7-alkylxanthines - Google Patents

Abstract

The solution concerns the one-step preparation of pharmacologically effective 1-(5-oxohexyl)-3-methyl-7-alkylxanthines from 1-methyl-5--(N-formyl-N-alkyl)-amino-6-aminouracils and 6-halohexanones using alkaline carbonates in an aprotic polar solvent environment at a temperature of 60°C to 180°C.

Description

The present invention relates to a process for the preparation of 1- (5-oxohexyl) -3-methyl-7-alkylxanthines of the general formula I

(1) wherein R is a linear or branched alkyl 0 _χ to C _{4 <The} compounds of formula I are characterized by a pharmacological effect on the cardiovascular system.

The preparation of the present compounds of formula I is described in the following basic ways:

1. alkylation of 3-methyl-7-alkylxanthines with 6-halogen-2-hexanones, as indicated for example by ČS AO

No. 237719, DOS 2330 742.

2. by cyclization of 1-methyl-3- (5-oxohexyl) -5-alkylamino-6-aminouracils [Jap. pat. 147091 /.

The process according to the invention is characterized in that ea is reacted with 1-methyl-5- (N-alkyl-N-formyl) amino-6-aminouracil of the general formula II

II / 11 / wherein R represents linear or branched alkyl to C 1-6, with 6-halohexanone of general formula III.

ch ₃ -co-ch ₂ -ch ₂ -ch ₂ -ch ₂ -x (111) wherein X is a chlorine or bromine atom, in the presence of alkali metal carbonates, preferably potassium carbonate in an aprotic polar solvent, preferably dimethylformamide, at elevated temperature 60 ° C to 180 ° C.

In one reaction step, alkylation occurs with a 6-halohexenone of formula III and cyclization to form a xanthine backbone. In reaction ea, it uses a molar ratio of 6-halohexanone of formula III to uracil of formula · ΙΙ 0.8 s 1 to 1.2 s 1 and a molar ratio of alkali carbonate to uracil of 2: 0.8 to 4: 1.

The advantage of the process according to the invention is the shortening of the reaction steps of the synthesis, since it is not necessary to prepare 3-methyl-7-alkylxanthine. In the following, the procedure is illustrated in the examples without being limited to these only.

Example 1 · 1- (5-oxohexyl) -3-methyl-7-propylxanthine

A mixture of 22.3 g of 1-methyl-5-N-formyl-N - [- propyl] -7-amino-6-aminouracil and 28 g of potassium carbonate is heated in 100 ml of dimethylformamide to a heat of 140 ° C. 14.4 g of 6-chloro-2-hexanone are then added over the course of 1 hour. The reaction mixture was stirred for another 6 hours. After separation, it is filtered off and concentrated in vacuo. 26 g, i.e. 86% of 1- (5-oxo-hexyl) -3-methyl-7-n-propylxanthine with a melting point of 62 DEG-64 DEG C., crystallized from tert-butyl methyl ether, are obtained.

Example 2 1- (5-Oxohexyl) -3,7-dimethylxanthine

19.6 g of 1-methyl-5- (N-methyl-N-formyl) amino-6-aminouracil and 20 g of 6-bromo-2-hexanone are treated at 120 DEG C. according to the procedure apologically to Example 1. 20 g, i.e. 70% of 1- (5-oxohexyl) -3,7-dimethylxanthine are obtained.

OS 267331 Bl

Example 3 1- (5-Oxohexyl) -3-methyl-7-isobutylxanthine

Following an analogous procedure to Example 1, 20.1 g of 1-methyl-5- (N-isobutyl-N-formyl) amino-6-aminouracil and 16.3 g of 6-chloro-2-hexanone were treated to give 28.2 g. g, i.e. 90% of 1- (5-oxohexyl) -3-methyl-7-isobutylxanthine.

Claims (3)

1. Process for the preparation of 1-(5-oxohexyl)-3-methyl-7-alkylxanthines of general formula I / ^{g /v} Cn3 where R is linear or branched alkyl up to _C4 , characterized by the fact that 1-methyl-5-[N-alkyl-N-formyl/amino-6-amino'ouracil of general formula II, And where R is a linear or branched C1 to _C4 alkyl, -hexanone of the general formula III /11/ is allowed to react with 6-halo-2ch ₃ -co-ch ₂ -ch ₂ -ch ₂ -ch ₂ -x /111/ where X is a chlorine or bromine atom, in the presence of alkali metal carbonates, preferably potassium carbonate in a polar aprotic solvent, preferably of dimethylformamide, at an elevated temperature of 60 °C to 180 °C. 2. The method according to point 1, characterized by; that the molar ratio of halohexanone of formula III to uracil of formula II is 0.8:1 to 1.2:1. 3. The method according to point 1 characterized by the fact that the molar ratio of alkali carbonate to uracil of formula II is 2:0.8 to 4:1.